Delta**1,4-16alpha-methyl steroids



United States Patent 3,426,128 A -IGa-METHYL STEROIDS Klaus Kieslich and Ulrich Kerb, Berlin-Charlottenburg,

and Gerhard Raspe, Berlin-Zehlendorf, Germany, assignors t0 Schering A.G., Berlin, Germany No Drawing. Continuation-impart of application Ser. No. 323,062, Nov. 12, 1963. This application Oct. 23, 1965, Ser. No. 504,233

Claims priority, application Germany, Feb. 22, 1961, Sch 29,274; July 27, 1963, Sch 33,627 The portion of the term of the patent subsequent to Jan. 31, 1983, has been disclaimed US. Cl. 424243 24 Claims Int. Cl. A61k 17/06; C07c 169/36 ABSTRACT OF THE DISCLOSURE A compound of the formula:

wherein R is acyl derived from a member selected from the group consisting of branched chain aliphatic carboxylic acids having at least four carbon atoms and straight chain aliphatic carboxylic acids having at least 6 carbon atoms in the acyl radical, R is selected from the group consisting of hydrogen and halogen and R is selected from the group consisting of hydrogen, halogen and methyl.

An example of the compounds of the invention is the following:

160a methyl 6a fiuor 9oz chloro A pregnadiene-l 13,21-diol-3,20-dione-2I-trimethylacetate.

The present invention relates to new A -16a-methyl steroids and to anti-inflammatory compositions utilizing such steroids as anti-inflammatory agent.

This application is a continuation in part of application Ser. No. 323,062, filed Nov. 12, 1963, now Patent 3,232,- 839, which is in turn a continuation in part of application Ser. No. 172,124, filed Feb. 9, 1962, and now abandoned.

It is a primary object of the present invention to provide new A -16a-methy1 steroids of the above type.

It is a further object of the present invention to provide new A -16a-methyl steroids which are useful as intermediates in the production of compounds of the steroids series, as for example 16a-methyl-A -6 pregnatriene-l1fl-21-dio1-3,20-dione-2l-acetate; 6,16a-dimethyl- 9 bromo A pregnadiene 115,21 diol 3,20 dione- 21-acetate; 6,16ot dirnethyl-A -pregnatriene-116,21-dio1- 3,20-dione-21-acetate; 6a-halogen-1'6a-methyl-A -pregcliene-l15,21-diol-3,20-dione-2l-pyranyl ether; 6a-methyl- 160a methyl A pregnadiene 115,21 diol 3,20- dione-21-pyranyl ether; 6a-halogen-l6a,21-dimethyl-A pregnadiene-l1B,21-diol3,20-dione; and 6a,16a,21-trimetliyl-A -pregnadiene-llp,21-diol-3,20-dione, and also to methods of producing such A -1 6a-methyl steroids. The compounds of the present invention can be used as intermediates in the production of the aforesaid com- "ice pounds by for example hydrogenating one or more of the bonds.

In addition, and this is a further object of the present invention, the compounds of the present invention have useful therapeutic properties by themselves, particularly as anti-inflammatory agents. In fact, the compounds of the present invention are not only generally useful as antiinflammatory agents, but these compounds, and particularly certain specific compounds among the new compounds produced according to the present invention, as will be more fully set forth below constitute highly superior anti-inflammatory agents.

Other objects and advantages of the present invention will be apparent from a further reading of the specification and of the appended claims.

With the above and other objects in view, the present invention mainly comprises as the new compounds useful as intermediates and as anti-inflammatory agents, compounds of the formula:

wherein R is selected from the group consisting of hydrogen and acyl, wherein acyl is preferably derived from an aliphatic carboxylic acid i.e., a branched chain aliphatic carboxylic acid or a straight chain aliphatic carboxylic acid having at least 4 carbon atoms in the alkyl group thereof, wherein R is selected from the group consisting of hydrogen and hydroxyl, R being hydroxyl only when X is -CH wherein X is selected from the group consisting of --CO--, -CHOH and CH wherein R is selected from the group consisting of hydrogen and halogen, and wherein R is selected from the group consisting of halogen and methyl when R is other than hydroxyl, and when R is hydroXy then R is selected from the group consisting of hydrogen, methyl and halogen.

The substituents R and R may be any of the halogens, i.e.-iodine, bromine, chlorine or fluorine, and when R; and R are both halogen, they may be the same halogen or different halogens. It is most preferred that R and R be either chlorine or fluorine, the most preferred compounds being those wherein R and/or R are fluorine.

The compounds of the present invention may be produced according to ditferent reaction mechanisms. According to one method, a compound of the formula:

(ID OHnOR I o o ij ll-position introduced hydroxyl group can, if desired, be converted in known manner by oxidation to the x0 group. The resulting compound is then converted into the corresponding A -steroid by treatment with dehydrogenating microorganisms or by known chemical dehydrogenation agents, and, in the event that the 21-p0sition is an hydroxyl group, the same can then, if desired, by selective acylation of the 21-position hydroxyl group be converted into the corresponding acylated compound.

The biochemical hydroxylation of the starting material can be carried out, for example, with Curvularz'a lunata, Mutant NRRL 2380.

The hydroxyl group introduced at the ll-position carbon atom can either be an a-oriented or ,B-oriented hydroxyl group. The hydroxyl group in the 11position, either a-oriented or B-oriented, can be further oxidized by means of oxidation agents normally used for this purpose, for example N-bromacetamide.

As 1,2-position dehydrogenating microorganism it is possible to use, for example, Bacillus Ientus, Mutant MB 284, or Corynebacterium simplex, Mutant ATCC 6946.

For acylation of the 2l-hydroxyl group, the most preferred acid is acetic acid, and other preferred acids are other lower aliphatic carboxylic acids such as propionic acid, butyric acid, caproic acid, enantic acid, undecylic acid, palmitic acid, phenyl propionic acid, pivalinic acid, tert. butylacetic acid, isobutyric acid, diethylacetic acid, dimethyl butyric acid, etc., or their reactable acid derivatives may be used in the reactions.

It is clear that the above method requires, in the case where both R and R are halogen, such as fluorine, and wherein X carries an oxygen function, for example in the production of compounds of the following formula:

III) CHzOR the use as starting material of a A -compound without the oxygen function in ll-position, but with the halogen atoms in 6-position and in 9-position, for example a starting compound of the following formula:

(IV) 01120 R tion halogen, e.g. fluorine atom, for example starting from compounds of the following formula:

(V) onion and after hydroxylating the same in ll-position converting the ll-position hydroxyl group into the 9a-fluoro-ll fi-hydroxy grouping to obtain the final desired ll-hydroxylated compound.

This method has the advantage that it makes no difference whether the primary ll-hydroxylation results in an Ila-hydroxyl group or an lip-hydroxyl group.

This method is illustrated by the following series of formulas, in which the method steps from the starting compound of Formula V to the respective ll-hydroxylated product is omitted in order to give a clearer picture. Method 1:

(IJHZOAC (III-I201: 00 CO HoW cm pix- (IJI-IQOAc (IIH2OAe CO (10 H0- CH3 "on;

l I i l Method 2:

(ilHzoR co How l "0H3 The anti-inflammatory action of the compounds of the present invention is particularly marked upon peroral ad- CH O OH O 2 R 2 R ministration, as shown 1n Table 2 below in which the C 00 action of 16a-methyl-6a,9a-difluoro-l-dehydrocorticos- 5 terone (I) is compared with 6a,9ot-difluor0-1-dehydro- H0 corticosterone (II) and 16a-methyl-9a-fiuoroprednisolone H (III). The anti-inflammatory action was determined on male rats weighing about 150 g. each. After oral administration of the active ingredient in the form of a guru BY 10 arabic-suspension by means of the known granuloma O O V pouch test. The obtamed value was compared 1n rela- 1 tion to hydrocortisone acetate (IV) which was used as F F the standard substance and was given an anti-inflammatory action equal to 1. (fHzOR $112012. CO CO --CH3 HO "CH3 0 TABLE Glycogen action Catebolic action Adrenal Inhibiting Active Arrestation of Activity Substance inflammation Compared Activity Compared Activity Compared Activity to IV Quotient to IV Quotient to IV Quotient 1, 300 Iv 1V 0. 023 110 XIV 0.083 200 XIV 0. 154 3. 8 IV 6 IV 1. 6 5 IV 1. 3 IV 10. 5

380XIV 30 IV 0. 079 SOXIV 0. 21 100 IV 0. 41s

The new compounds of the present invention possess marked therapeutic activity in the treatment of inflammatory diseases.

The compounds of the present invention have remarkably little side reactions, for example with respect to influence of the mineral balance, despite the mineralocorticoid type of structure of the compounds.

This is illustrated by the following table wherein WD 50 (active dose 50) is the dose of the tested substance which, according to A. Robert and I. E. Nezamis (Acta Endrocrinologica, vol. 25 (1957), page 105), gives an attenuation of the exudate formation of 50% compared to the untreated controls, and wherein Doc represents desoxycorticosterone The value of an active substance is arrived at not only by determining the superior absolute values of the desired action, for example the anti-inflammatory action, but it is also determined in general by the extent of the undesired side effects of a substance, it being well known that with a produced increase in activity in a series there is also obtained a corresponding increase in the side effects.

In the instant case it was therefore quite surprising that the significant increase of the anti-inflammatory action of the compound I, namely 16a-methyl-6a,9u-difluoro-1- dehydrocorticosterone is accompanied by only a slight increase in the undesired glycogen, catabolic and adrenal inhibition side effects (compare columns B, C and F of Table 2).

The glyconeogenetic action was determined on mice using the customary liver glycogen test. The catabolic and adrenal inhibiting actions were tested on growing female rats weighing about 4050 g. over a 14-day period following subcutaneous administration of the test substance. The applied dosage to determine the degree of side effect was so chosen that with compounds I, II and III the same anti-inflammatory action was obtained. Hydrocortisone acetate again served as the standard substance for this test. The values, particularly the surprisingly low corresponding activity quotients prove that the compound of the present invention, compound I, as compared to the comparison substances I I and III, with regard to the undesired side effects exhibits markedly superior properties.

Because of the exceedingly low side effects, particularly on the glycogen balance, the catabolic effect and the adrenal inhibiting eifect, the compounds of the present invention are not only suitable for the treatment of external inflammatory diseases, such as skin diseases of all types, but are also suitable for the treatment of internal inflammatory diseases, such as kidney inflammation, liver inflammation, polyarthritis, and the like diseases, by oral administration.

The anti-inflammatory action of the compounds of the present invention is further illustrated in Table 3 below in which compounds of the present invention were compared in the granuloma pouch test to hydrocortisone acetate (V), which was given the anti-inflammatory activity of 1, after oral administration of the tested compounds. The values are set forth in the table:

TABLE 3 Po. 16a-methyl-6a-fluoro-9a-chlor0A pregnadiene-l 1 8,21-diol-3,20- dione (V) 100 300 X VI 16a-methyl-6a-fluoro-9a-chloro-A pregnadiene-l15,21-diol-3,20-dione-2lacetate (VI) 130 X IV 16a-methyl-9a-chloro-A -pregnadiene- 11/5,21-diol-3,20-dione (VII) 100 130 x IV l6a-methyl-9a-chloro-A -pregnadienel15,2l-diol-3,20-dione-2l-acetate (VIII) 38 x IV The compound 6u-fiuoro-l6a-rnethyl-A -pregnadiene- 11/3,2l-diol-3,20-dione (IX) was also compared to 6ozfluoro-A -pregnadiene-l1;8,21-diol-3,20-dione (X) with respect to the desired anti-inflammatory action, as well as with respect to the undesired glycogen and catabolic side effects. The values are set forth in Table 4 below in which the compounds tested were compared with hydrocortisone acetate (IV), which was given an anti-inflammatory action of 1.

The anti-inflammatory action of the compounds of the application were observed in comparison to that of hydrocortisone acetate and l6a-methyl-6a-fluor-1,4-pregnadiene-l113,21-diol-3,20-dione-acetate with respect to their effect on experimentally induced arthritis in the rat paw.

The anti-inflammatory activity was determined in 80-100 g. male rats. Each rat was first subjected to a volumetive type of measurement of his right paw (control value). Edema was induced by injection of heat killed and freeze-dried Mycobacterium butyricum (0.05 ml. of a 0.5% suspension in paraffin oil). After 24 hours the same paw was again measured and then the test substance in the amounts indicated (in the form of their solution in castor oil) injected intramuscularly and the paw measured daily for size change.

The following compounds of Table are quoted as an illustration for the inflammatory action of the compounds of the application.

11,8,21-diol-3,20-dione-21cnanthate.

TABLE 5-Contiuued Duration Dosis, of rug/kg. Activity in Days V IGa-methyl-(ia-fluor-l,-pregnadiene- 10 65 11B,21-diol3,20-dione-Ql-undecylate.

VI lfia-methyl-fia'iiuor-l,-pregnadiene- 100 11fi,21-di0l-3,20-dione-21-palinitate.

VII ltia-methyHia-iluor-l,4-pregnadiene- 10 27 1119,21-diol-3,ZO-dione-Zl-trimethylacetate.

VIII lea-methyl'6a-fiuor-9a-ehloro-l,4- 1 21 pregnadiene11B,21-diol-3,20- dione-21-butyrate.

IX.. loa-methyl-fia-fiuor-SJa-chloro-l,4- 1 28 pregnadiene-l1B,21-di0l-3,20-dione- 21-capr0ate.

X lfia-uiethyl-fia-fluor-Qa-chloro-l, 4- 1 60 pregnadiene-11fi,21-diol-3,20-dione 21-undecylate.

XI 16mmethyi'6a-iiuor-9a-chloro-1,4- 1 27 pregnadiene-llli,21-diol-3,20-dione ZI-triUethylaeetate.

XII. 16a-methyl-6a,9a-difluor-i,A-pregnadi- 1 16 ene-l113,21-diol-3,20dione-21-caproate.

XIII 16a-metl1yl-6a,t)a-difluor-1, i-pregnadi- 1 21 one-l119,2l-diol-3,20-dione2lenanthate.

XIV 16mmethyl-6a,9a-diilu0r-1,4-pregnadi- 1 36 ene-llB,21-di0l-3,20-di0ne-21- nndeeylate.

XV IGu-methyI-Ga,9udifluor-1,4-prcgnudi- 1 10 ene-llB,2i-diol-3,20-dione-21-trimethylacctate.

The anti-inflammatory action of the compounds of the invention was determined in healthy human subjects 18-38 years of age in the following manner:

The backs of the test subjects were prepared in a manner so as to produce a specific design using therefor a 2 cm. broad strip of Tesafilm. The design as it appeared on the back included areas of stripped and normal skini.e., areas of irritation corresponding to the design pattern. Thereafter each of the test substances in salve form containing a specified concentration of active substance was applied onto the back of the subject, an area of 4 cm. being covered. Over this 4 cm. area the same amount of salve--namely, about 25 mg. of the salve containing the designated concentrati0nwas applied.

The vasoconstriction as well as the other anti-inflammatory actions were then measured. This included the degree of activity and the duration of activity. To this end the backs of the test subjects were photographed using Kodak color film and the color value of the portion of the back which had been treated so as to have imparted thereto a design photographed both before and after treatment with the salve. The untreated or normal skin was given a color value of 100, and the stripped skin a color value of 0.

Following application of the salve, the anti-inflammatory activity was measured by comparing newly determined color values with the color values previously obtained. The activityi e., recognizable or unquestionable anti-inflammatory activitywhich was produced by the minimum concentration of active agent was noted. In addition, the time in which the desired activity was attained following application of the salve to the skin was also recorded. Further, the time taken to obtain a color value of 50 in the stripped skin was also noted (this value will be set out later in the table in the column WD.) The results of the tests are set out in the following table. As a standard hydrooortisone was employed.

TABLE Concen- Onset of tration actlvlty Substance of active (time WDw agent in elapsed weight in hours) .percent 3 5 Hydrocortrsone 8 3% 5% 16amethyl-6a-fiuor-A pregnadiene- 0. 001 2 3% 110,21-diol-3,20-dione-2Lbutyrate. 0. 0001 1 3 lfizx-methyl-fia-fluonA -pregnad1ene- 001 1 2 11,8,21-diol-3,20-d1one-21-tr1methyl- 0001 2 3% acetate. lfia-methyl-fia-fiuor-A -pregnad1ene- O- 1 1 2% 11B,21diol-3,20-dlone 2l-phenylpro- 0' 01 1 2% iona e. IGE-rnethyl-Ga-fluor-A -pregnadiene- 0. 01 1% 4 115,21-di01-3,20-d1one-21-onanthate. 0. 01 2 4 IGa-methyI-Ba-fiuQr-A -pregnad1ene- 0. 1 3 4A 1113,21-dio1-3,20-d1one-21-capronate. 0. 01 3 45 16a-methyl-tia-fluqr-tla-chlor-A -preg- 001 1 2 nadiene-1lB,21-d1ol-3,20-d1one-21-tr1- 0. 0001 1 2% methylacetate.

From the above table it is clearly apparent that the compounds in accordance with the invention have an onset of activity and a WD significantly superior to that of hydrocortisone. Further the compounds in accordance with the invention in most instances show these properties at minimal concentrations (significantly less than that required to produce the noted effect with hydrocortisone).

For medical purposes the compounds of the present invention can be used in all common administration forms, for example as lotions, salves, powders or tinctures for external application, or as tablets, powders, suspensions, capsules and as injectible preparations for internal administration. The medicinal preparations are produced in known methods by working up of the active agent with the common pharmaceutical carriers.

The following examples are given to further illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples.

EXAMPLE I (a) Production of l6a-metl1yl-4-pregnene-11,6,21-

diol-3,20-dione l 6u-methylcorticosterone) A fermenter of rust-free steel having a 50-1iter capacity is charged with 30 liters of a nutrient solution contammg:

4.4% glucose (starch sugar) 1.0% malt extract 0.3% NaNO 0.1% KH PO 0.05% KCl 0.05 MgSO 0.002% FeSO 0.5% corn steep sterilized for one half hour at 120 C. and after cooling, inoculated with a spore suspension of Curvularia lunata which is obtained by rinsing a seven day corn culture (15 g. corn) with approximately 100 cc. of physiological sodium chloride solution.

After two days of culturing at 25 C. under stirring (220 revolutions per minute) and ventilating (1.65 m. hour), 1.8 liters of the obtained culture are removed under sterile conditions and introduced into a fermenter of the same size charged with 28.2 liters of a nutrient solution containing:

4.4% glucose (starch sugar) 1.0% malt extract 0.3% NaNO 0.1% KH PO After 24 hours cultivation under stirring and ventilation as described above, 7.5 g. of 16a-rnethyl-desoxycorticosterone obtained by saponification of the corresponding 2l-acetate and melting at 102l04 C. in 200 cc. of ethanol are added and fermented under the same conditions for 28 hours.

The course of the fermentation is tested by removal of samples, which are extracted with methyl isobutyl ketone. The extract is analyzed by paper chromatography in a system of dioxane+toluene/propylene glycol.

After the end of fermentation (28 hours) the culture broth is filtered off by suction over a large suction filter. The mycelium residue is washed with water several times. The filtrate is extracted three times, each time with 10 liters of methyl isobutyl ketone. The extract is concentrated under vacuum in a circulating evaporator and in a round flask carefully dried under vacuum. The residue is crystallized from acetone/isopropyl ether. The melting point is 157158 C. (fermentation yield=60%).

The pure product yield obtained after a second crystallization and chromatography of the mother liquor on silica gel amounts to 53 of the theoretical.

Analysis.Ca1cu1ated for C22H3204 240: 15,400: C, 73.3; H, 9.0; O, 17.7. Found: C, 73.1; H. 9.2; O, 17.2.

(b) Production of 1Ga-methyl-IA- regnadiene-I lB,21-diol- 3,20-dione (=16a-methyl-l-dehydro-corticosterone) A fermenter made of rust-free steel and having a 50- liter capacity is charged with 30 liters of a nutrient solution containing 1% glucose and 0.2% corn steep and sterilized as described in Example I(a) above. It is then inoculated with a bacterial suspension of C0ryn:ebaoteri um simplex, which is obtained by rinsing a bouillon agar surface plate of 64 cm. with 7 cc. of physiological sodium chloride solution.

After 24 hours of culturing under the conditions of Example I(a) above, 1.8 liters of the obtained culture are removed under sterile conditions and transferred into a fermenter containing 28.2 liters of the same medium. At the same time there is added a solution of 7.5 g. of 16-methyl-corticosterone of Example I(a) in cc. of ethanol and the same is fermented under the same conditions for 16 hours at 25 C.

The course of fermentation (14 hours) is again tested by removal of samples which are extracted with methyl isobutyl ketone. The extracts are analyzed by polarographic methods.

The cultured broth, without filtration, is extracted three times, each time with 10 liters of methyl isobutyl ketone. The extract is worked up as described under I(a) above. The residue, after recrystallization two times from acetone/isopropyl ether results in 4.5 g. of a crystalline product melting at 191/192-1935 C.

By chromatography of the mother liquor an additional 2 g. is obtained. The total yield amounts to 87% of the theoretical.

Analysis.Ca1cu1ated for C22H3DO4 7242 15,100: C, 73.75; H, 8.4; O, 17.85. Found: C, 73.7; H, 8.9; O, 18.0.

(0) Production of 16a-methyl 1,4 pregnadiene-lljigZldiol-3,20-dione-2l-acetate (=16oz methyl-l-dehydrocorticosterone-Zl acetate) 500 mg. of 16 a-methyl-l-dehydro-corticosterone obtained from Example I(b) above are allowed to stand in 3 cc. of pyridine with 1.5 cc. of acetanhydride for two hours at room temperature and thereafter 20 cc. of 8% sulfuric acid are introduced at 0 C. After one hour the crystalline product is filtered off under suction, washed with water and dried. There is obtained 558 mg, of a crude product which is recrystallized from a small amount of ethanol. The final yield is 492 mg. of the compound 11 which melts at 204205 C. The yield corresponds to 87% of the theoretical.

Analysis.Calculated for C H O (400.5), 6242: 15,020: C, 72.0; H, 8.1; O, 19.95. Found: C, 71.7; H, 8.4; O, 20.4.

EXAMPLE II (a) Production of l6a-methyl-A -pregnene-21- ol-3,11,20-trione 2 g. of l6a-methylcorticosterone obtained according to Example I(a) are dissolved in 120 cc. of 96% acetone, mixed with 1.4 g. of N-bromacetamide are allowed to stand for three hours at room temperature. 600 cc. of water are stirred in and the reaction mixture is then extracted four times, each time with 11 cc. of methylene chloride. The extract is washed until neutral, dried over sodium sulfate and concentrated under vacuum. The residue (2.1 g.) is subjected to chromatography over silica gel. 1.4 g. of the crude ll-keto compound are eluated with CH Cl :CHCl (1:1) and 'CHCl There is obtained after recrystallization from chloroform-isopropyl ether 900 mg. of the product melting at 176/179181 C. The yield amounts to 44% of the theoretical.

Analysis.-Calculated for C2ZH3004 6237: 15,120: C, 73.7; H, 8.4; O, 17.9. Found: C, 71.7; H, 8.5; O, 17.6.

(b) Production of 16a-methyl-A -pregnadiene-2 1-ol-3, 11,20-trione from l6a-methyl-M-pregnene-Z1-ol-3,1 l, 20-trione 20-trione 16rx-methyl-A -pregnene 21 ol 3,11,20 trione, produced according to Example II(a), are dehydrogenated by means of Corynebacterium simplex as described in Example I(b) to obtain 16ot-methyl-A -pregnadiene-21- ol-3,11,20-trione, which is identical with the product produced acording to Example II(c), below.

(0) Production of 16a: methyl-A -pregnadiene-21-ol-3, 11,20-trione from 16a-methyl A pregnadiene-l 1p, 2l-diol-3,20-dione 1 g. of 16a methyl A dehydro corticosterone (see Example II(a) are oxidized and further worked up as described in Example I(b) with 60 cc. of 96% acetone and with 720 mg. of N-bromacetamide for 3 hours. There is thus obtained 1.2 g. of the crude product, which after chromatographic purification on silica gel and recrystallization from ethyl acetate-hexa11e yields 430 mg. (43% of the theoretical) of the pure ll-keto compound which melts at 160/161163 C.

Analysis-Calculated for C H O (356.46), 6 15,120: C, 74.2; H, 7.9; O, 17.9. Found: C, 73.5; H, 8.2, O, 17.8.

(d) Production of 16u-methyl-A -pregnadiene-2l-ol- 3,11,20-trione-21-acetate 550 mg. of 16a-methyl-A -dehydrocorticosterone-21- acetate obtained from Example I(c) are dissolved in 92 cc. of 96% acetone, oxidized by means of 1.1 g. of N- bromacetamide for three hours at room temperature as described in Example II(a), and then further worked up. There is thus obtained 550 mg. of the crude product which is subjected to chromatography on silica gel. The methylene chloride eluate contains 390 mg. of the crystalline substance, which after recrystallization from a small amount of ethanol results in 286 mg. of the pure product which melts at 207/209-210" C.

Analysis.-Calculated for C24H3OO5 623'] 14,820: C, 72.3; H, 7.6; O, 20.1. Found: C, 71.6; H, 7.9; O, 20.1.

12 EXAMPLE III (a) Production of 16a-methyl-A -pregnene-14a, 2l-diol-3,20-dione A fcrmenter of rust-free steel having a 50 liter capacity is charged with 30 liters of a nutrient solution containing:

5% saccharose 1% beet sugar molasses 0.2% NaHCO 0.1% KH PO 0.05 KCl 0.001% FeSO,

0.05% MgSO 0.5% corn steep (pH 7) heated for one half hour at 120 C. to sterilize it and after cooling is innoculated with a spore suspension of Curvularia lunata which is obtained by rinsing a seven day corn culture (15 g. corn) with approximately cc. of physiological sodium chloride solution.

After two days of growth at 25 C. under stirring (220 revolutions per minute) and ventilation (1.65 m. /hour), 1.8 liters of the obtained culture are removed under sterile conditions and introduced into a 50 liter fermenter containing 30 liters of a nutrient solution containing:

5% saccharose 1% beet sugar molasses 0.2% NaNO 0.1% KH PO After 24 hours of growth under stirring revolutions per minute) and ventilation (8 m. /hour), 7.5 g. of 16a-methyl-A -pregnene-21-ol-3,20-dione in 200 cc. of ethanol are added and the fermentation is continued for 28 hours under the same conditions.

The course of fermentation is tested by the removal of samples, which are extracted with methyl isobutyl ketone. The extracts are subjected to paper chromatography in a system of dioxane-l-toluene/ propylene glycol for analysis.

After the end of the fermentation the culture broth is filtered off under suction and extracted with methyl isobutyl ketone. The extract is concentrated under vacuum and the residue is subjected to chromatography on silica gel to separate the 11,3- and the Mix-hydroxylated compounds. The fractions with 16a-methyl-A -pregnene-14a, 21-diol-3,20-dione are acetylated as the crude product, as follows:

6 g. of the crude product in 20 cc. of pyridine with 10 cc. of acetanhydride are allowed to stand for 3 hours at room temperature and then cc. of 8% sulfuric acid at 0 C. are stirred in. After 1 hour the crystalline product is filtered oil under suction, washed with water, dried, and then recrystallized from isopropyl ether. 1.7 g. of the compound is obtained, the compound melting at 192/193-194 C.

Analysis.-Calculated for C H O 6240 15,200: C, 71.7; H, 8.5; O, 19.9. Found: C, 70.4; H, 9.0; O, 20.1.

(b) Production of 16a-methyl-A -pregnadiene-14a, 21-diol-3,20-dione l6a-methyl-A -pregnene-14a,21-diol 3,20 dione are dehydrogenated with Corynebacterium simplex as described in Example I(b), thereby obtaining 16a-methyl- A -pregnadiene-l4a,21-diol-3,20-dione.

EXAMPLE IV (a) Production of 16a-methyl-6a-chloro-A -pregnene- 11fi,21-diol-3,20-dione 16a-methyl-6u-chloro-A -pregnene-2l-ol-3,20-dione are, analogously to Example I(a), hydroxylated in llfl-position. The hitherto unknown starting material 16a-methyl- 6a-chloro-A -pregnene-2l-ol-3,20-diose (melting point: l7]l73 C.), and its 2l-acetate (melting point 144- 145.5 C.) is obtained from l6a-methyl-A -pregnene-3fl- (b) Production of l6ot-methyl-6u-chloro-A -pregnadiene-l 15,2 l-diol-3,20 -dione 16a methyl 6oz chloro A pregnene 115,21 diol- 3,20-dione is dehydrogenated with Corynebacterium simplex as described in Example I(b), and there is thus obtained 1a-methyl-6a-chloro-A -pregnadiene-115,2l-diol- 3,20-dione.

EXAMPLE V (a) 16a-methyl-6a-fluoro-A -pregnese115,21-diol- 3,20-dione 16cc methyl 60c fluoro A pregnene 21 ol 3,20- dione-Zl-acetate (M.P.: 132/134138 C., UVe =l5,- 000) is hydroxylated with Curvularia lunata in 1l5-p0sition using the fermentation method previously described in Example I(a), whereby the 21-acetate group is simultaneously saponified. The hitherto unknown starting material 16a-methyl-6a-fluoro-A -pregnene-21-ol-3,20-dione- 2l-acetate is obtained from 16a-methyl-A -pregnene- 35,21-diol-20-one-21-acetate (M.P. 152-154" C.) by the addition of brorno-fluorine (from N-bromacetamide and hydrogen fluoride) onto the 5-6 double bond, oxidation of the 35-hydroxyl group with chromic acid, introduction of the A -double bond by splitting of the hydrogen bromide and acid isomerization of the 65-fluoro substituent to the 16a-methyl-6ot-fluoro-A -pregnene-21-0l-3,20-dione- 21-acetate.

By chromatographic purification on silica gel the 160: methyl 60c fluoro A pregnene 115,21 diol- 3,20-dione is: M.P. 166/167-171" C.; e =14,()00.

(b) l6ot-methyl-6 a-fluoro-A -pregnene-l 15,21-diol- 3,20-dione-2 l-acetate By reaction of the compound of Example V(a) with acetanhydride in pyridine at room temperature as described in Example I(c), the acetate is obtained and recrystallized from ethyl acetate. M.P. 248/249-251 C.;

(c) 16a-methyl-6u-fluoro-A -pregnadiene-1 15,21-dio1- 3,20-dione 16a methyl 6a fluoro A pregnene 115,21 diol- 3,20-dione is dehydrogenated with Corynebacterium simplex as described in Example I(b). The extraction residue is subjected to chromatography on silica gel and after recrystallization there is obtained from a methylene chloride-isopropyl ether 16a methyl 6oz fluoro A pregnadiene-ll5,2l-diol-3,20-dione. M.P. 180/ 181182 C. 241=15,320.

(d) 16a-methyl-6a-fluoro-A -pregnadiene-l15,21-diol- 3,20-dione-21-acetate 16oz methyl 6a fluoro A pregnadiene 115,21- diol-3,20-dione are acetylated as described in Example I(c) above and the product is recrystallized from methylene chloride/isopropyl ether. M.P. 232/ 233-235 C.; 20=15,36O.

(a) 16a-methyl-6a-fiuoro-A -pregnene-l4a,21-diol- 3,20-dione The mother liquor of Example V(a) upon additional chromatography permits the isolation of l6a-methyl- M-pregnene-l4ot,2l-diol-3,20-dione. After recrystallization from ethyl acetate: M.P. 250/252-253 C.; 235 14,000.

1 4 (b) 16a-methyl-6a-fluoro-A -pregnene-14u,21-di0l- 3,20-dione-2 l-acetate 16a methyl 6a fluoro A pregnene 14a,2l diol- 3,20-dione are acetylated as described in Example I(c) above, and recrystallized from ethanol/isopropyl ether. M.P. 179/180-182 C.; e ==14,400.

(c) 16a-methyl-6a-fluoro-A -pregnadiene-1411,21-di0l- 3,20-dione 16a methyl 6oz fluoro A pregnene :,21 diol- 3,20-dione are dehydrogenated with Corynebacterium simplex as described in Example I(b). The extraction residue is subjected to chromatography on silica gel and after recrystallization from ethyl acetate there is obtained 16a methyl 6a fluoro A pregnadiene 1411,21- diol-3,20-dione. M.P. 241/242-243" C.; e =16,500.

(d) 16a-methyl-6a-fluoro-A -pregnadiene-l4a,2l-diol 3,20-dione-2 l-acetate 16oz methyl 60c fluoro A pregnadiene 1404,21- diol-3,20-dione are acetylate-d as described in Example I(c) and recrystallized from ethyl acetate. M.P. 220/ 223- 236 C.; e =15,500.

EXAMPLE VII (a) 16u-methyl-A -pregnadiene-l4a,2l-diol3,20-dione Analogously to Example I(b) 30 liters of a sterile nutrient solution containing 0.1% yeast extract, 0.5% corn steep and 0.2% glucose are innoculated with a bacterial suspension of Bacillus lentus Mutant MB 284. After 24 hours of culturing, 1.8 liters of the culture broth are transferred into 28.2 liters of a sterile medium of the same composition. At the same time, 7.5 g. of 16amethyl-A pregnene-14a,2l-diol-3,20-dione in cc. of ethanol are added and the fermentation is continue-d for 30 hours at 25 C. The culture broth is further worked up as described in Example I(b), whereby there is obtained 5.2 g. of crystalline crude product which is recrystallized from ethyl acetate. The yield is 3.7 g., and the compound melts at 242/244-246 C.

Analysis.Calculated for C H O (358.5), e =15,- 750: C, 73.8; H, 8.4; O, 17.8. Found: C, 73.6; H, 8.5; O, 18.5.

(b) 16amethyl-A -pregnadiene- 14a,2 1-diol-3,20-dione- 21-acetate 320 mg. of 16a-methyl-A -pregnadiene-14a,21-diol- 3,20-dione are acetylated in 3 cc. of pyridine with 1.5 cc. of acetic acid anhydride for 2 hours at room temperature, as described in Example 1(0), and then further worked up. The crude product is recrystallized from ethyl acetate. The compound melts at 208/ 209210 C.

Analysis.Calculated for C H O (400.52), e =15,- 830: C, 72.1; H, 8.6; O, 19.84. Found: C, 71.96; H, 9.97; O, 19.95.

EXAMPLE VIII (a) l6a-methyl-9a-fiuoro-M-pregnene-1 15,21-dio1- 3,20-dione As described in Example I(a), 7.5 g. of 16a-methyl- 9a-fluoro A pregnene-21-ol-3,20-dione-2l-acetate, obtained from l6a-methyl-A -pregnene-115-2l-diol-3,20 dione (see Example I(a)) by acetylating with acetic anhydride in pyridine followed by reaction of the thus formed ZI-aceta-te (melting at 193.5194.5 C.) with hydrogen fluoride in pyridine at 0 are fermented for 36 hours with Curvularia lunam (Mutant NRRL 2380), whereby the 21- acetate group is simultaneously saponified and the broth is further worked up. The residue is extracted with methyl isobutyl ketone, subjected to chromatography on silica gel and there is obtained from chloroform/ethyl acetate (2:1) an eluate containing the 115-hydroxyl compound, which is further dehydrogcnated as the crude product.

1 (b) 16a-methyl-9a-fiuoro-A -pregnadiene-115,21- diol-3 ,20-dione 16a-methyl 90c fiuoro-A -pregnene-11fl,21-diol-3,20- dione obtained as the crude product under Example VIII(a) above, is fermented with Bacillus lentus for 30 hours and further worked up, as described in Example VII(a). The residue is extracted with methyl isobutyl ketone and there is obtained as the crude product 160:- methyl-9wfluoro-A -pregnadiene 115,21 diol 3,20- dione.

(c) 16a-methyl-9a-fluor0-A -pregnadiene-1119,21-diol- 3 ,20-dione-21-acetate 16a-methyl 90c fiuoro-A -pregnadiene-l1/3,21-diol-3, 20-dione are acetylated as described in Example I(c) as the crude product, and further worked up. The obtained crude acetate is recrystallized from isopropyl ether/methyl chloride. The melting point=220226 C.

UV: 623g EXAMPLE IX (a) 6oz,16a-dimethyl-A -pregnene-11fl,21-diol-3,20-dione As described in Example I( a) 6u,16a-dimethyl-A -pregnene-2l-ol-3,20-dione-2l-acetate (M.P. 120121 C.) is fermented with Curvularia lun'ata in llp-position, whereby the 21-acetate group is simultaneously saponified. The hitherto unknown starting material 6B,16a-dimethyl-A pregnene-21-ol-3,20-dione-2l-acetate is obtained from 6,8,16a-dimethyl-pregnane-3,8,5a-diol 20 one (R. P. Graber Chem. and Ind., 1960, 1478) by treatment with bromine in ether, reaction of the introduced 21-bromine atom with potassium acetate, oxidation of the 3,6-position hydroxyl with chromic acid, introduction of the A -double bond by dehydration with hydrogen chloride in acetic acid whereby the 6/3-methyl group is simultaneously isomerized.

By chromatography on silica gel the 6a-16a-dimethyl- M-pregnene-l1fi,21-diol-3,20-dione is isolated. M.P. 165- 167.5 C.

(b) 60a, 1 6a-dimethyl-A -pregnene-1 15,21- diol-3,20-dione-2 l-acetate By reaction with acetanhydride in pyridine at room temperature as described in Example I(c) the acetate is obtained. M.P. 194-1955 C.

(c) 6m,16wdimethyl-A -pregnadiene-11/3, 2l-diol-3,20-dione 6a,16a-dimethyl A pregnene-l1,8,21-diol-3,20-dione is dehydrogenated with Corynebacterium simplex as described in Example I(b).

( d) 6a,16a-dimethyl-A -pregnadiene-1 15,21- diol-3,20-dione-2 1 -acetate 6a,16u-dimethyl A pregnadiene-ll/3,21-di0l-3,20- dione is acetylated as described in Example I(c).

EXAMPLE X.-Reaction method 1 illustrated above (a) Production of 6a-fiuoro-16a-methyl-4,9(11)- pregnadiene-2 1-ol-3 ,20-dione-21-acetate g. of 6a-fiuoro-16a-methyl-A -pregnene-1113,21-di01- 3,20-dione-2l-acetate are dissolved in 8.8 cc. of pyridine and 50 cc. of dimethylformamide and warmed under nitrogen to a temperature of +70 C. 4.42 cc. of methyl chloride are then added and the temperature is maintained at 8085 C. for 30 minutes. After cooling to 20 C. the solution is stirred into 900 cc. of ice water. The precipitate is filtered oil under suction and dried. The crude product amounts to 9.25 g. (97.5% of the theoretical). The melting point is 160/164167 C. a +1l2.3 CHCl 1 6 (b) Production of 6a-fiuoro-9a-bromo-16a-methyl-A pregncne-11fl,21-diol-3 ,20-dione 21-acetate A solution of 6.02 g. of dibromodimethylhydantoin in 10 cc. of distilled water and 25.4 cc. of dioxane is added at 20 C. to a solution of 10 g. of 6a-fiuoro-l6u-methyl- 4,9(11)-pregnadiene-21-ol-3,20 iione-2l-acetate in cc. of dioxane, and then the mixture is stirred for an additional 10 minutes. A solution of 0.845 cc. of perchloric acid in 13.4 cc. of distilled water is then added and in time intervals of 15 minutes each, 2 cc. of the reaction mixture each time is titrated with N Na S O solution against starch. The reaction (60-75 minutes) is ended when no more HOBr is needed. 3.77 g. of sodium acetate 3H O and 2.42 g. of sodium sulfite in 25 cc. of water are added for neutralization, whereby the temperature is maintained at a maximum of 23 C. After the neutralization, the test with potassium iodide starch paper should give a negative result and the pH value is between 5.6 and 7. cc. of methanol is then added. The inorganic precipitate is filtered off under suction and the filter residue subsequently washed with a mixture of 26.8 cc. of methanokdioxane (1:1). 442 cc. of distilled water is added under stirring to the filtrate at +15 C. The precipitate is stirred for two hours at +5 C. and the precipitated substance then filtered off under suction and dried at 20 C. under vacuum over KOH. The yield is 10.8 g. (86.5% of the theoretical) of the crude product, The melting point is l62164 C. (with decomposition).

(0) Production of 6a-fiuoro-l6ot-methyl-9,B,11/3-oxido- M-pregnene-Zl-ol3,20-dione-2l-acetate 10 g. of 6a-fluoro-9a-bromo-l6a-methyl-A -pregnene- 115,21-diol-3,20-dione-2l-acetate are added at 50 C. to a solution of 8.7 g. of potassium acetate in 104 cc. of ethyl alcohol and the reaction mixture is cooked under refluxing for 75 minutes. After cooling to +10 C., 247 cc. of water are added dropwise in such manner that the temperature of the reaction solution does not increase to above +15 C. The reaction mixture is subsequently further stirred for 2 hours under ice cooling and filtered off under suction. The crude product is recrystallized from methanol with the addition of carbon. The yield is 7.32 g. (88% of the theoretical). The melting point is 153/1545- l56 C. e =l3,000; u +72.1 (CHCl (d) Production of 6 a a,9a-difluoro- 1 6a-methyl-A pregnene-l15,2l-diol-3,20-dione-2l-acetate 8 cc. of hydrogen fluoride are added at 0 C. to a mixture of 90 cc. of chloroform and 10 cc. of ethanol, and subsequently during a time period of 15 minutes a solution of 10 g. of 6a fluoro-16a-methyl-9fl,115-oxido-A pregnene-Z1-o1-3,20-dione-2l-acetate in 90 cc. of chloroform are added. The reaction mixture is then further stirred for 2 hours at 0 to 5 C. For neutralization there is added at a maximum temperature of 45 C., 30.75 g. of potassium carbonate dissolved in 30 cc. of water. After the addition of a 5% sodium bicarbonate solution, the neutralization is completed to a pH value of 6.5. The chloroform solution is again washed -with water, dried and concentrated to dryness under vacuum. The residue is recrystallized first from methanol-chloroform with the addition of carbon and subsequently from chloroformbenzene. The yield is 5.0 g. (47% of the theoretical). The melting point is 229/232-234 C. a +133.8 CHCl 233:16,000.

(e) Production of 6u,9a-dif1uoro-16a-methyl-A pregnadiene-l1,6,21-di0l-3,20-dione 16cc methyl 6a,9a-difluoro-A -pregnene-1113,21-diol- 3,20-dione-21-acetate (melting point=229/232234 C. (with decomposition)) is dehydrogenated in 1,2-position by means of Bacillus lemus, Mutant MB 284, whereby the 2l-acetate group is simultaneously saponified. (It is possible under the same conditions to start with the free 21- hydroxyl compound.)

For this purpose a fermenter made of stainless steel having a 50 liter capacity is charged with 30 liters of a nutrient solution of 0.1% yeast extract, 0.5% cornsteep and 0.2% glucose, heated for one half hour at 120 C. for sterilization purposes, and after cooling, inoculated with a bacterial suspension of Bacillus lentus MB 284.

After 24 hours of growth at 28 C. under stirring (220 revolutions per minute) and aeration (1.65 m. /hour), 1.8 liters of the obtained culture is removed under sterile conditions and transferred with 28 liters of the same sterilized nutrient medium into a fermenter of the same slze.

Simultaneously, 6 g. of 16a-methyl-6a,9a-dilluoro-A pregnene-l113,21-diol-3,20-dione-2l-acetate in 200 cc. of dimethylformamide are added and the fermentation is continued for 50 hours under the same conditions.

The course of the fermentation is tested by removal of samples which are extracted 'with methyl isobutyl ketone. The extracts are analyzed by thin layer chromatography using a system of benzene/ethyl acetate (4:1).

After further working up analogously to Example I there is obtained an oily crystalline residue which is subjected to chromatography on silica gel. The 16u-methyl- 60,9a difluoro-A -pregnadiene-11fi,21-diol-3,20-dione is eluated with ethyl acetate-chloroform (1:2), it is recrystallized from ethyl acetate/ ether and then formed to melt at 240/242-244" C. The yield is 60% of the theoretical. E237=16,600-

EXAMPLE XI.-The reaction mechanism of method 2 illustrated above (a) Production of 6u-fluoro- 1-6 a-methyl-A pregnatriene-Z1-ol-3,20-dione-2l-acetate 10 g. of 6rx-fi-uoro-16u-methyl-A -pregnadiene-115,21- dil-3,20-dione-acetate are dehydrated as described in Example X(a). The compound melts at 164-165 C. (from methanol). 6 16,750.

(b) Production of 6a-fluoro-9u-bromo-16a-methyl- A -pregnadiene-11,8,21-diol-3 ,20-dione-21 acetate g. of 6a-fluoro-16a-methy1-A -pregnatriene-21- ol-3,20-dione-2l-acetate are converted to the corresponding bromohydrin as described in Example X(b) The crude product melts at 120126 C. (with decomposition).

(c) Production of 6a-fluoro-16wmethyl-9BJ 1B- oxido- A -pregnadiene-2l-ol-3,2-0-dione-21-acetate 10 g. of 6a fluoro-9ot-brorno-16a-methyl-A -pregnadiene-l113,21-diol-3,20-dione-21-acetate are converted into the corresponding 9,115-epoxide as described in Example X(c). The crude product melts at 145149 C.

(d) Production of 6u,9 x-difiuoro- 1 6a-methyl-A pregnadiene-l1,8,2l-diol-3,20 dione-2l-acetate 10 g. of 6c: fluoro 16a-methyl-9fl,11B-oxido-A pregnadiene 21-ol-3,20-dione-2l-acetate are treated with hydrogen fluoride as described in Example X(d). The crude product is recrystallized from ethyl acetate. The melting point is 259/260261.5 C. 62:37:16,400.

EXAMPLE X II (METHOD 1) (a) Production of 6a-fiuoro-16a-methyl-A -pregnene- 11fl,21-diol-3,20-dione A fermenter made of stainless steel and having a 50 liter capacity is charged with 30 liters of a nutrient solution of:

4.4% glucose (starch sugar) 1% cornsteep liquor 0.3% NaNO 0.1% KH PO and heated for one half hour at 120 C. for sterilization, and after cooling inoculated with a Spore suspension of Aspergillus ochraceus, which is obtained by rinsing a 7-day 18 corn cob culture (15 g. corn) with about cc. of physiological sodium chloride solution.

After l-day growth at 30 C. under stirring (220 revolutions per minute) and aeration (1.65 mfi/hour), 1.8 liters of the obtained culture is removed under sterile conditions and transferred into a fermenter of the same size with 28.2 liters of a nutrient solution of 1% glucose and 1% soy flour. At the same time, 7.5 g. of 6m-fiuoro-16amethyl-A -pregnene-21-ol-3,20-dione dissolved in 100 cc. of ethanol are added and fermented under the same conditions for about 48 hours.

The course of the fermentation is determined by removal of samples which are extracted with methyl isobutyl ketone. The extracts are analyzed by thin layer chromatography.

After the end of the fermentation the material is further worked up as described in Example I(a). The crude product can be recrystallized from ethyl acetate without chromatography. The melting point is 178.5-179.5 C.

(b) Production of 6ix-fiuoro-16a-methyl-A -pregnene- 111,21-diol-3,20-dione-21-acetate 10 g. of 6a-fluoro-16u-methyl-A -pregnene-:,2l-di0l- 3,20-dione are dissolved in 20 cc. of dimethyl formamide and under stirring mixed with 600 mg. of

and 8 cc. of acetanhydride. After subsequent stirring for an additional 2 hours at room temperature the reaction solution is poured into water. The resulting precipitate is filtered off under suction, dried and recrystallized from ethyl acetate-isopropyl ether. The melting point is 169.5- 170 c. ,,=14,900.

(c) Production of 6a-fluoro-16a-methylpregnadiene-Z1-ol-3,20-dione-2l-acetate 4.22 g. of bromacetamide are added to a solution of 10 g. of 6a-fiuoro-16a-methyl-A -pregnene-11a-21-diol-3, 20-dione-21-acetate in 100 cc. of pyridine at 20 C. and subsequently stirred for an additional 10 minutes. After cooling to +5 C., S0 gas is conducted into the solution at this temperature until, upon testing of the reaction mixture with potassium iodide starch paper a negative result is obtained. During the gas introduction a substance precipitates in the reaction mixture. It forms into a thick crystalline broth. To complete the precipitation, 200 cc. of water and 10 C. are added after completion of the gas introduction. The precipitate is filtered off under suction after several hours of standing washed with dilute pyridine-free hydrochloric acid and washed with water until neutral. The crude produce is recrystallized from methylene chloride-ethyl acetate. The melting point is /165168 C. e =15,200.

The further working up proceeds as described in Examples X(b)-X(c).

EXAMPLE XIII (METHOD 2) (a) Production of 6a-fluoro-16u-methyl-A -pregnadiene- 11a,21-diol-3,20-dione 7.5 g. of 60: fluoro 16cc methyl-N-pregnene-l111,21

diol-3,20-dione are fermented with Bacillus lentus as described in Example X(c). The crude product can be recrystallized without chromatography from ethyl acetateisopropyl ether. The melting point is 255/257260 C. 6237 16,200-

(b) Production of 6a-fluoro-16a-methyl-A -pregnadiene- 11u,21-diol-3,20-dione-21-acetate 10 g. of 6oc-fluoro-16ot-methyl-A -pregnadiene-11a,21- diol-3,20-dione are selectively acetylated in 2l-position as described in Example XlI(b). The melting point is 230/233-235 C. e =15,8OO.

() Production of 6OL-fiL1OI'O-I6OL-IllfithYI-A -pregnatriene-21-ol-3,20-dione-2l-acetate 10 g. of 6a-fiuoro-16ot-methyl-A -pregnadiene-1101,21- diol-3,20-dione are dehydrated as described in Example XII(c). The melting point is 164165 C. (from metha- DUI). E238:16,750.

The further working up proceeds as described in Examples XI(c)XI(d).

EXAMPLE XIV (a) Production of 16ot-methyl-u-fiuoro-9ot-chloro-A pregnadiene-l 1 [1,2 1-diol-3,20-dione-2 l-acetate 1 g. of 16a-methyl-6a-fluoro-A -pregnatriene-Z1- ol-3,20-dione-21-acetate (produced as described in Example XI(a)) are dissolved in 52.4 cc. of dioxane, mixed with 3.53 g. of N-chlorosuccinimide and 26.3 cc. of 1 N perchloric acid and stirred for 6 hours at 25 C. under argon. The solution is poured into ice water containing sodium thiosulfate, stirred for 1 hour and the precipitated substance is filtered off under suction, washed until neutral, dried and recrystallized from methanol/methylene chloride. The melting point is 252 C. (with decomposition). The yield is 0.79 g. UV e =16,100.

400 mg. of 16a-methyl-6a-fluoro-9a-chloro-A -pregnadiene-l1,8,21-diol-3,20-dione-2l-acetate are suspended in 1.6 cc. of methylene chloride and 1.6 cc. of methanol and mixed at O5 C. under argon with a solution of 24 mg. of potassium hydroxide in 0.8 cc. of methanol. The reaction mixture is stirred for 80 minutes at 05 C., neutralized with several drops of glacial acetic acid, diluted with methylene chloride, washed with Water until neutral and evaporated. The residue is recrystallized from methanolmethylene chloride. The melting point is 254 C. (with decomposition). The yield is 265 mg. UV 6237:-16,2O0.

EXAMPLE XV (a) Production of 16a-methyl-9a-chloroA -pregnadiene-l 16,21-diol-3,20-dione-21-acetate 11.6 g. of 16ot-methyl-A -pregnadiene-11,8,21-diol-3, -dione-21-acetate are dissolved in 50 cc. of dimethyl formamide and 11 cc. of pyridine, mixed with 5.1 cc. of methane sulfochloride and stirred for 1 hour at 80 C. After cooling to 20 C., the solution is stirred into ice water, the precipitate filtered off under suction, dried and recrystallized from acetone/hexane. The obtained 16:!- methyl A -pregnatriene-2l-ol-3,20-dione-2l-acetate melts at 157-158 C. The yield amounts to 80% of the theoretical.

(b) Production of I6tl-IIICthyI-9Ot-ChIOIO-A -PI'CgIIH- diene1113-2l-diol-3,20-dione-2l-acetate 3 g. of 16a methyl A -pregnatriene-Zl-ol-3,20- dione-Zl-acetate are dissolved in 157 cc. of dioxane, mixed with 10.6 g. of N-chlorosuccinimide and 79 cc. of 1 N perchloric acid and stirred at 30 C. for 6 hours under argon. The solution is stirred into ice water containing sodium thiosulfate, the precipitate filtered oil under suction, dried and recrystallized from isopropyl ether/ methylene chloride. The obtained 16ot-methy1-9a-chloro- A pregnadiene-l 1,8,21-dio1-3,20-dione-21-acetate melts at 215 C. (with decomposition). The yield amounts to 65% of the theoretical. UV e =15,500.

(0) Production of 16a-methyl-9u-chloro-A -pregnadiene-l 1,3,2 l-diol-3,20-dione 800 mg. of 16a-methyl-6tx-chloro-A -pregnadiene-11B, 2l-diol-3,20-dione-2l-acetate are saponified as described in Example X(b) and further worked up. The residue is recrystallized from methanol-methylene chloride. The melting point is 234 C. (with decomposition). The yield amounts to 60% of the theoretical. UV e =15,3()0.

20 EXAMPLE XVI 16a-methyl-6ot-fiuor-A -pregnadiene-1 1p, 2 1-diol-3 ,20-dione-2 1 -enanth ate 2 g. 160a methyl-6ot-fiu0r-A -pregnadiene-115,21-diol- 3,20-dione in 8 ml. pyridine and 4 ml. enanthate acid anhydride were allowed to stand at room temperature for 16 hours. The enanthate which crystallized out was separated by suction filtering and after drying, the enanthate was recrystallized from a mixture of methylene chloride and isopropylether. Melting point 226-227 C. UV: e =16,20O. The yield amounted to of theory.

EXAMPLE XVII 16a-methyl-6ot-fluor-A -pregnadiene-l 1 t3, 21-diol-3,20-dione-2l-trimethylacetate 2 g. 16:1 methyl-6a-fluor-A -pregnadiene-115,21-di0l- 3,20-dione in 20 ml. pyridine and 2.5 ml. pivalin acid chloride were stirred for 16 hours at 5 C. and then poured into ice water. The separated precipitate was taken up in acetic ester, washed with 1 N sulfuric acid, N/ 10 soda lye and water, evaporated and crystallized out of carbon tetrachloride. Melting point 171-173 C. UV: e =l5,6OO. The yield amounted to of theory.

EXAMPLE XVIII 16ot-methyl-6a-fiuor-N' pregnadiene-1 1,8, 21-diol-3,20-dione-2l-butyrate 2 g. of 16a methyl-a-fiuor A pregnadiene-11fl,21- diol-3,20-dione in 8 ml. pyridine were reacted with 4 ml. butyric acid anhydride and the reaction mixture worked up as set out in Example XVI. The l6ot-methyl- 6a-fluor-A -pregnadiene 11fl,21 diol 3,20 dione-Zlbutyrate thus obtained was crystallized out of a mixture of methylene chloride and isopropylether. Melting point -168 C. UV: e =l6,300. The yield amounted to 85% of theory.

EXAMPLE XIX 16a-methyl-6a-fiuor-A -pregnadiene-1 1 ti, 21-diol-3,20-dione-21-t.butylacetate 1 g. l6ot-methyl-6a-fiuor-A -pregnadiene-1lfi,21-diol- 3,20-dione and 2 ml. t.butylacetyl chloride were stirred for 16 hours at 7 C. in 25 ml. pyridine. The reaction mixture was then worked up as set out in Example XVII. Following recrystallization from isopropylether/ methylene chloride, 750 mg. 16a-methyl-6a-fluor-A pregnadiene-l15,21-diol-3,20-dione-21t.butylacetate were obtained. Melting point 211213 C. UV: e =15,850.

EXAMPLE XX 16a-methyl-6a-fluor-A -pregnadiene- 1 1,8, 21-dio1-3,20-dione-2l-phenylpropionate 3 g. 16oz methyl-6a-fluor-a -pregnadiene-1113,21-diol- 3,20-dione were reacted with 6 ml. phenylpropionic acid chloride in 75 ml. pyridine at 4 C. The reaction mixture was stirred for a further 15 hours at -4 C. Then it was poured into ice water and extracted with methylene chloride. The methylene chloride solution was washed with dilute sulfuric acid, N/ 10 soda lye and water, dried and evaporated in vacuo. The resulting crude 16a-methyl- 6a-fiuor-A -pregnadiene-115,21 diol 3,20 dione 21- phenylpropionate was chromatographed on silica gel and thereafter crystallized out of isopropylether/methylene chloride. Melting point 238239 C. UV: e =I4,300, e =16,60(). The yield amounted to 75%.

hydride were allowed to stand for 48 hours at 20 C. The reaction mixture was worked up as described in 21 Example XVII. The crude 16a-methyl-6tx-fl-uor-A -pregnadiene-l1,8,21-diol-3,20-dione-2l-undecylate was taken up in pentane and crystallized from isopropyl ether. Melting point 66-67 C. The yield amounted to 95% of theory.

EXAMPLE XXII 16a-methyl-6a-fluor-A -pregnadiene-1 1,8, 2 l-diol-3,20-dione-2 l-p almitate 18 g. 16a-methyl-6u-fluor-A -pregnadiene-115,21-diol- 3,20-dine were stirred together with 1 ml. palmitic acid chloride in 20 ml. pyridine for 48 hours at 7 C. and the reaction mixture worked up as described in Example XVII. The obtained 16a-methyl-6a-fl'uor-A -pregnadiene- 11B,21-diol-3,20-dione-2l-palmitate was crystallized out of isopropyl ether. Melting point 93-94 C. The yield amounted to 80% of theory.

EXAMPLE XXIII 16a-methyl-6a-fluor-9a-chlor-A -pregnadiene-1 1,8,21- diol-3 ,20-dione-21-undecylate 2 g. 160: methyl-6u-fluor 90c chlor-A -pregnadiene- 11B,21-diol-3,'20-dione in 15 ml. pyridine were reacted with 3.2 g. undecylic acid anhydride and worked up as described in Example XXI. Melting point l40.5141.5 C. The yield amounted to 90% of theory.

EXAMPLE XXIV 6a,9a-difluor-16a-methyl-1,4-pregnadiene-1 1,8,21-

diol-3,20-dione-2l-enanthate 400 mg. 6u,9a-difluor-16tx-methyl-1,4-pregnadiene-11B, 21-diol-3,20-dione were dissolved in 1.6 ml. pyridine and reacted with 0.8 ml. enanthic acid anhydride. The reaction mixture was permitted to stand for 24 hours at room temperature. The solution was then stirred at 0 C. with 20 ml. 8% sulfuric acid. The mixture which formed was then extracted with methylene chloride. The extract was then successively washed with water, NaCHO solution and water, dried over Na SO and evaporated to dryness in vacuo. The resulting residue was crystallized from acetone isopropylether. Melting point 213-214 C. UVIe =16,800. The yield amounted to 425 mg.

EXAMPLE XXV l6a-methyl-6a-fluor-9u-chlor-A -pregnadiene-l 1,8,21- diol-3,20-dione-2 l-caproate (a) 10 g. 16a-methyl-6a-fluor-A -pregnadiene-115,21- diol-3,20-dione-2l-caproate (M.P. 242245 C.) prepared from the 21-OH compound, by reaction with caproic acid anhydride/pyridine at room temperature; (yield 90%) were dissolved in 50 ml. dimethyl formamide and 8.8 ml. pyridine and thereafter reacted with 4.4 ml. methanesulfochloride as described in Example XV(a).

The obtained 16oz methyl 6a fiuor-A -pregnatriene-21-ol-3,20-dione-caproate was recrystallized from isopropylether/methylene chloride. Melting point 120 122 C. UVZe =16,900. The yield amounted to 85% of theory.

(b) 7.8 g. 16u-methyI-Ga-fiuor-A -pregnatriene- 21-ol-3,20-dione-caproate were dissolved in 410 ml. dioxane and then reacted with 27.5 g. N-chlorosuccinimide and 205 m1. 1 N perchloric acid as described in Example XIV(b). The 160s methyl-6a-fluor-9a-chlor-A -pregnadiene-l15,21-diol-3,20-dione-2l-caproate was crystallized from isopropyl ether/methylene chloride. Melting point 154.5l55.5 C. UV2e =16,0O0. The yield amounted to 60% of theory.

EXAMPLE XXVI 16a-methyl-6a-fiuor-9a-chlor-A -pregnadiene-11fl,21-

diol-3,20-dione-2 l-t-butylacetate (a) 1 g. 16a-methyl-6a-fluor-A -pregnadiene-11fl,21- diol-3,20-dione were dissolved in 25 ml. absolute pyridine under 1 cc. cooling reacted with 2 ml. t-butyl-acetylchloride (content of about 5% thionyl chloride) and allowed to stand for 16 hours at 20 C. Thereafter the reaction mixture was diluted with methylene chloride and successively washed with dilute sulfuric acid, water 1% NaHCO solution and water. The methylene chloride solution was thereafter evaporated in vacuo and the resulting 16amethyl 6a fluor A114,9 11) pregnatriene 21 ol 3,20- dione t butylacetate crystallized from methylene chloride/isopropyl ether. Melting point 167168 C. UV2e =16,700. The yield amounted to 65% of theory.

(b) 800 mg. 16u-methyl-6u-fiuor-A -pregnatriene- 21-ol-3,ZO-dione-t-butyl-acetate were dissolved in 42 ml. dioxane and reacted under stirring and at 30 C. with 2.8 g. N-chloronecinimide and 21 ml. 1 N-perchloric acid for hours. The reaction mixture was worked up as described in Example XIV(a). The thus obtained 16ccmethyl-6u-fluor-9u-chlor-A -pregnadiene-1113,21 dial-3, 20-dione-2l-butylacetate was crystallized from isopropyl ether/methylene chloride. Melting point 23l.5232 C. UV:e =16,400. The yield amounted to of theory.

EXAMPLE XXVII l6a-methyl-6tx-fluor-9a-chlor-A -pregnadiene-1 15,21- diol-3,20-dione-2 l-trimethylacetate (a) 3 g. 16a-methyl-6a-fiuor-A -pregnadiene-11 8,21- diol-3,20-dione were dissolved in ml. dry pyridine and under ice cooling reacted with 6 ml. trimethyl-acetyl chloride and 0.06 ml. thionyl chloride. The reaction mixture was permitted to stand for 16 hours at room temperature. Thereafter the reaction solution was stirred into 1.5 liters of ice water, extracted with methylene chloride and the methylene chloride phase successively washed with dilute sulfuric acid (1+9), N/ 10 soda lye and water, dried and evaporated. The resulting crude l6a-methyl-6a-fluor- A -pregnatriene-Z1-ol-3,20-dione trimethyl acetate was chromatographed over silica gel and crystallized from methylene chloride-isopropyl ether. Melting point 209- 210 C. UVZe =16,300. The yield amounted to 95% of theory.

(b) 4 g. 16a-methyl-6a-fluor-A -pregnatriene-Z1- ol-3,20-dione-trimethyl-acetate were dissolved in 250 ml. dioxane and then reacted with 14 g. N-chlorsuccinimide and ml. 1 N perchlorine acid. The reaction mixture was stirred for 4 hours at 30 C. under argon and worked up as described in Example XIV(a). The obtained 16a methyl 6a fluor 90c chlor A pregnadiene- 115,21-diol-3,20-dione-2l-trimethylacetate was crystallized out of acetonehexane. Melting point 230.5232 C. UVIe =16,l00. The yield amounted to 60% of theory.

EXAMPLE XXVIII 16u-methyl-6a-fluor-9a-ch1or-A -pregnadiene-1 15,21- diol-3 ,20-dione-21-butyrate (a) 10g. 16a-methyl-6a-fluor-A -pregnadiene-116,21- diol-3,20-dione-2l-butyrate (M.P. -186 C. prepared from the 21-OH reaction product with butyric acid anhydride/pyridine, yield 94% of theory) were dissolved in 50 ml. dimethyl formamide and 8.8 ml. pyridine and then reacted with 4.4 ml. methane sulfonic acid chloride. The reaction and working up of the reaction product were carried out according to Example XV(a). The resulting 16a methyl 60 fluor M41901) pregnatriene 21 ol- 3,20-dione butyrate was crystallized from isopropyl ether/methylene chloride. Melting point 131.5132.5 C. The yield amounted to 80% of theory.

(b) 6.2 g. 16a-methyl-6a-fiuor-A pregnatriene- 2l-ol-3,20-dione butyrate were dissolved in 325 ml. dioxane and reacted with 22 g. N-chlorsuccinimide and 163 ml. 1 N perchloric acid analogous to the procedure disclosed in Example 14(b). The 16a-methyl-6a-fluor-9uchlor-A -pregnadiene 1 113,21 diol-3,20-dione-2l-butyrate which was thereby formed was crystallized from isopropylether/methylene chloride. Melting point 210-212 23 C. (decomp). UV: e =16,000. The yield amounted to 60% of theory.

EXAMPLE XXIX 16a-methyI-Gu-fiuQr-AU-pregnadiene- 11fi,2A1-diol-3,20-dione-2l-caproate 10 g. 16a-methy1-6ot-fiuor-A -pregnadiene-11,8,21-diol- 3,20-dione in 40 ml. pyridine were allowed to stand with 20 ml. caproic acid anhydride for 12 hours at about 22 C. The caproate which crystallized out was separated by suction filtering, washed and dried and recrystallized from ethylene chloride. Melting point 242-245 C. UV: 6 16,200. The yield amounted to 95% of theory.

EXAMPLE XXX 6a,9a-difiuor-16a-methyl-1,4-pregnadiene- 11,8,21-diol-3,-20-dione-2l-undecylate 400 mg. 6a-9a-difluor-16a-methyl-l,4-pregnadiene-11,5, 21-diol-3,20-dione were introduced into a solution of 650 mg. undecylic acid anhydride in 3 ml. pyridine. The solution was allowed to stand for 48 hours at room temperature and thereafter reacted with about 5 ml. water and extracted with ether. The extract was washed with 2 N H 50 2 N NaOH and with water. The washed extract was dried and then evaporated to dryness. The residue was washed with pentane and crystallized from isopropyl ether. Melting point 100/-10l102 C. UV: e :16,60'0. The yield amounted to 369 mg.

EXAMPLE XXXI 611-9 u-difluor- 1 6a-methyl- 1 ,4-pregnadiene- 1113,2l-diol-3,20-dione-2l-trimethylacetate 200 mg. 6u,9ot-difluor-16ot-methyl-1,4-pregnadiene-11,8, 2l-diol-3,20-dione were dissolved in 2 ml. pyridine and reacted with 0.25 ml. trimethylacetic acid chloride. The solution was then allowed to stand at from to 5 C. for 16 hours. Thereafter it was stirred for 2 hours at about 22 C. and then poured into ice water. After 3 0 minutes of stirring, the crystals which had separated out were removed by suction filtering and dissolved in acetic ester. The acetic ester solution was washed successively with 5% acetic acid, water, NaHCC solution and water, dried over Na SO and concentratet in vacuo. The concentrate was crystallized from isoprt pyl ether methylene chloride. Melting point 217/218-2 19 C. UV: 6 17,200. The yield amounted to 1 85 nzg.

EXAMPLE XXXII 16 a-methyl-9a-fluor-1,4-pregnadiene-1 1 5,21- diol-3,20-dione-2 l-trimethylacetate 2 g. 16a-methyl-9a-fluor-1,4-pregnadiene-115,21-diol- 3,20-dione in 10 ml. pyridine were reacted with 2.5 ml. pivalinic acid chloride as described in Example XVII. Melting point of the isolated .ZI-trimethylacetate 205.5- 206.5 C. The yield amounted to 80% of theory.

EXAMPLE XXXIII 16a-methy1-6a-fluor-1,4-pregnadiene-1 15,21- diol-3,20-dione-2 l-dimethylacetate 1 g. 16a-methyl-6a-fiuor 1,4-pregnadiene-115,21-dio1- 3,20-dione in 10 ml. pyridine were reacted with 1.2 ml. isobutyric acid chloride as described in Example XVII. Melting point of the isolated Zl-dimethylacetate 187- 188 C. UV: e =:15,900. The yield amounted to 90% of theory.

EXAMPLE XXXIV 16a-methyl-6a-fluor4,4-pregnadiene-1 15,21- diol-3,20-dione-2 l-diethylacetate 1 g. 16a-methyl-6a-fluor-1,4-pregnadiene- 1113,21-diol- 3,20-dione in 5 ml. pyridine and 2.5 ml. diethylacetic acid anhydride were reacted for 20 hours at room temperature. Then the reaction mixture was worked up as described in Example XVII. Melting point of the isolated 24 ZI-diethylacetate 230-233 C. (crystallized out of ethylacetate). The yield amounted to 780 g.

EXAMPLE XXXV 16a-methyl-6a-fiuorlApregnadienn-l 1fl,2 ldiol-3,20-dione-21,2',2'-dimethylb ityrate To a solution of 3 g. 16a-methyl-6a-f--1or-1,4-pregnadiene-l 1,8,21-di0l-3,20-dione in 75 ml. pyridine were added 6 ml. 2,2-dimethylbutyric acid ch11 ride at 5 C. The reaction mixture was stirred for l hours at +4 to 6 C. and thereafter worked up as a :scribcd in Example XVII. Melting point of the isolated Zl-2,2-dimethylbutyrate 161163 C. UV: e =15, 00. The yield amounted to of theory.

EXAMPLE XXXVI 16a-methyl-6a,9u-difluor-1,4-pregnadiene- 116,2 1-diol-3 ,20-dione-2 1 -caproate 1 g. l6a-methyl-6u,9ot-difluor-1,4-pregnadiene-l15,21- diol-3,20-dione in 1 ml. pyridine and 2.5 ml. caproic acid anhydride were reacted for 4 hours at room temperature. Thereafter the reaction mixture was added into 10 ml. 8 volume percent sulfuric acid at 0 C. and stirred one hour. The 21-caproate which crystallized out was separated by suction filtering, washed and dried and recrystallized from ethylene chloride. Melting point 223-224" C. UV: e =16,4Q0. The yield amounted to 950 mg.

Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can by applying current knowledge readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential charactcristics of the generic or specific aspects of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims.

What is claimed as new and desired to be secured by Letters Patent is:

1. A compound of the formula:

CHaOR wherein R is acyl derived from a member selected from the group consisting of branched chain aliphatic carboxylic acids having at least four carbon atoms and straight chain aliphatic carboxylic acids having at least 6 carbon atoms in the acyl radical, R is selected from the group consisting of hydrogen and halogen and R is selected from the group consisting of hydrogen, halogen and methyl.

2. A therapeutic composition comprising an active antiinflammatory agent and a pharmaceutically acceptable carrier therefor, the anti-inflammatory agent being constituted by a compound of the formula CHzOR wherein R is acyl derived from a member selected from the group consisting of caproic, enanthic, undecylenic, palmitic, dimethyl acetic, trimethyl acetic, diethyl acetic, tert. butyl acetic, phenyl propionic and dimethyl butyric acid and wherein R is selected from the group consisting of hydrogen, chlorine and fluorine and R is selected from the group consisting of hydrogen and fluorine.

3. A method of treating inflammatory conditions comprising administering to a subject afliicted therewith a therapeutic composition comprising an active anti-inflammatory agent and a pharmaceutically acceptable carrier therefor, the said anti-inflammatory agent being constituted by a compound of the formula CH2OR wherein R is acyl derived from a member selected from the group consisting of caproic, enanthic, undecylenic, palmitic, dimethyl acetic, trimethyl acetic, diethyl acetic, butyl acetic, phenyl propionic and dimethyl butyric acid and wherein R is selected from the group consisting of hydrogen, chlorine and fluorine and R is selected from the group consisting of hydrogen and fluorine.

4. 16a methyl-6a-fluor-A -pregnadiene-115,21-diol-3, 2 '0-dione-21-enanthate.

5. 161x methyl-6a-flu0r-A -pregnadiene-115,21-diol-3, 20-dione-21-trimethylacetate.

6. 16a methyl-6a-fluor-A -pregnadiene-115,21-dio1-3, 20-dione-2l-t.butylacetate.

7. 16a-methyl-6a-fluor-A pregnadiene 115,21 diol- 3,20-dine-21-phenylpropionate.

8. 16a-methyl-6a-fluor-A -pregnadiene 115,21 diol- 3,20-dione-2l-undecylate.

9. 16a-methyl-6a-fiuor-A -pregnadiene 115,21 diol- 3,20-dione-21-palmitate.

10. 160a methyl fluor-9a-chlor-A -pregnadiene- 1 15,21-diol-3,20-dione-2l-undecylate.

11. 6oc-9a-difiu01' 16a methyl-1,4-pregnadiene-115, 21-diol-3,20-di0ne-2l-enanthate.

12. 160: methyl 60c fluor-9a-chlor-A -pregnadiene- 1 15,21-diol-3 ,20-dione-21-caproate.

13. 16a methyl 60c fluor-9a-chlor-A -pregnadiene- 115,2l-diol-3,20-dione-2l-butylacetate.

14. 16a methyl 61x fluor-9a-chlor-A -pregnadiene- 1 15,21-diol-3,20-dione-2l-trimethylacetate.

15. 16a methyl 60 flu0r-A -pregnadiene-115,21- diol-3,20-dione-21-caproate.

16. 611-: -difluor 16a methyl-1,4-pregnadiene-115, 21-diol-3,2'0'-dione-2l-undecylate.

17. out-9a difluor 16a methyl-1,4-pregnadiene-115, 21-diol-3,2 0-dione-2l-trimethylacetate. v

18. A therapeutic composition comprising as active anti-inflammatory agent a compound according to claim 1 and comprising a pharmaceutically acceptable carrier.

19. A method of treating inflammatory conditions comprising administering to a subject afliicted therewith a therapeutic composition comprising as active anti-inflammatory agent a compound according to claim 1 in dosage unit form together with a pharmaceutically acceptable carrier.

20. 16a methyl-9a-fluor-1,4-pregnadiene-115,21-diol- 3,20-dione-2l-trimethylacetate.

21. met-hyl-6a-fluor-1,4-pregnadiene-115,21-diol- 3,20-dione-2l-dimethylacetate.

22. 160: methyl-fia-fluor-1,4-pregnadiene-115,21-diol- 3,20-dione-2l-diethylacetate.

23. 1600 methyl-6a fluor-1,4-pregnadiene-115,21-diol- 3,20-dione-21-2',2-dimethylbutyrate.

24. 16oz methyl 604,90: difluor-1,4-pregnadiene-115, 21-diol-3,20-dione-2l-caproate.

References Cited UNITED STATES PATENTS 3,232,839 2/1966 Kieslich et al. 16 777 HENRY A. FRENC I-I, Primary Examiner.

US. Cl. X.R. 

